Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the US, approximately 3-4 million individuals are affected by this disease costing the US economy over $40 billion dollars per year. The cause of this debilitating neurodegenerative disease is presently unknown. However, a large body of evidence indicates that at least some if not all AD cases are due to genetic factors which can be passed from one generation to the next. Genetic analysis of families with multiple cases of presenile AD suggests that autosomal dominant genes are responsible for at least some occurrences of the disease. In these families, off-spring of affected persons appear to be at 50% risk of inheriting a familial AD (FAD) gene and developing AD. The long range goal of this research project is to identify the underlying cause of AD by identifying the genes responsible for the genetic form of this disease. The first step in attaining this goal is to locate the chromosomal regions containing FAD genes by establishing a linkage relationship between a known genetic marker and the FAD genes. Identification of FAD genes will facilitate establishing the etiology of AD, possibly lead to better diagnostic methods, and potentially provide a rationale for designing therapeutic and preventative measures. Three genetic loci have been identified which are heritable factors in AD: the amyloid precursor protein (APP) gene, a chromosome 14 AD locus, and a susceptibility locus at the ApoE gene/region on chromosome 19. The primary efforts of this research project are to further characterize these loci and to identify additional loci involved in AD inheritance as follows: 1) Additional kindreds will be identified in which the inheritance of AD genes can be studied; 2) Genomic screening methods will be used to map the gene responsible for early-onset autosomal dominant AD in the Volga German families; 3) Additional genes responsible for late- onset familial AD will also be sought by genomic scanning methods; 4) The role of ApoE, gender, and lipoproteins will be investigated as risk factors for late-onset AD; 5) The ApoE/CI/CII region of chromosome 19 will be characterized to identify the region in disequilibrium with ApoE; 6) FAD families will be screened for APP mutations to provide additional information for further clinical and neuropathologic characterization.